U.S. patent number 10,213,421 [Application Number 13/851,538] was granted by the patent office on 2019-02-26 for pharmaceutical formulations comprising ccr3 antagonists.
This patent grant is currently assigned to Alkahest, Inc.. The grantee listed for this patent is Alkahest, Inc.. Invention is credited to Alfred Fetscher, Jochen Matthias Scher.
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United States Patent |
10,213,421 |
Fetscher , et al. |
February 26, 2019 |
Pharmaceutical formulations comprising CCR3 antagonists
Abstract
The present invention relates to pharmaceutical compositions
containing one or more compounds of formula 1 ##STR00001## wherein
R.sup.1 is H, C.sub.1-6-alkyl,
C.sub.0-4-alkyl-C.sub.3-6-cycloalkyl, C.sub.1-6-haloalkyl; R.sup.2
is H, C.sub.1-6-alkyl; X is an anion selected from the group
consisting of chloride or 1/2 dibenzoyltartrate j is 1 or 2.
processes for the preparation thereof, and their use to treat
diseases connected with the CCR3 receptor.
Inventors: |
Fetscher; Alfred (Betzenweiler,
DE), Scher; Jochen Matthias (Warthausen,
DE) |
Applicant: |
Name |
City |
State |
Country |
Type |
Alkahest, Inc. |
San Carlos |
CA |
US |
|
|
Assignee: |
Alkahest, Inc. (San Carlos,
CA)
|
Family
ID: |
49292482 |
Appl.
No.: |
13/851,538 |
Filed: |
March 27, 2013 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20130266646 A1 |
Oct 10, 2013 |
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Foreign Application Priority Data
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Apr 4, 2012 [EP] |
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12163078 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P
11/00 (20180101); A61K 9/4858 (20130101); A61K
9/2013 (20130101); A61P 31/00 (20180101); A61P
37/06 (20180101); A61P 5/14 (20180101); A61P
7/04 (20180101); A61P 7/06 (20180101); A61P
21/00 (20180101); A61K 9/2031 (20130101); A61K
9/2018 (20130101); A61K 9/4866 (20130101); A61K
31/4545 (20130101); A61P 1/00 (20180101); A61P
27/02 (20180101); A61P 37/02 (20180101); A61P
11/06 (20180101); A61K 9/2813 (20130101); A61P
43/00 (20180101); A61P 19/02 (20180101); A61P
13/12 (20180101); A61K 9/2054 (20130101); A61K
9/0053 (20130101); A61K 9/2853 (20130101); A61P
37/08 (20180101); A61K 9/2866 (20130101); A61P
1/04 (20180101); A61P 37/00 (20180101); A61P
29/00 (20180101); A61K 9/1617 (20130101); A61K
9/2027 (20130101); A61P 11/02 (20180101); A61P
35/00 (20180101); A61P 9/00 (20180101); A61P
17/00 (20180101); A61P 17/06 (20180101); A61K
9/2077 (20130101); A61K 9/284 (20130101); A61P
21/04 (20180101) |
Current International
Class: |
A61K
31/4545 (20060101); A61K 9/28 (20060101); A61K
9/68 (20060101); A61K 9/00 (20060101); A61K
9/48 (20060101); A61K 9/16 (20060101); A61K
9/20 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0468187 |
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Jan 1992 |
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EP |
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2002501052 |
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Jan 2002 |
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JP |
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2002501898 |
|
Jan 2002 |
|
JP |
|
2006137718 |
|
Jun 2006 |
|
JP |
|
WO 1996020699 |
|
Jul 1996 |
|
WO |
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2006083390 |
|
Aug 2006 |
|
WO |
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2006091671 |
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Aug 2006 |
|
WO |
|
2006095671 |
|
Sep 2006 |
|
WO |
|
2007116313 |
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Oct 2007 |
|
WO |
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2008092681 |
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Aug 2008 |
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WO |
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2009145721 |
|
Dec 2009 |
|
WO |
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WO 2010052727 |
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May 2010 |
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WO |
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2010115836 |
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Oct 2010 |
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WO |
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2012045803 |
|
Apr 2012 |
|
WO |
|
2013149986 |
|
Oct 2013 |
|
WO |
|
2013149987 |
|
Oct 2013 |
|
WO |
|
Other References
Shaikh, R.H., et al., "Stability of Pharmaceutical Formulations",
Pak. J. Pharma. Sci., 1996, pp. 83-86. cited by examiner .
Lin, S.L., et al., "Preformulation Investigation I: Relation of
Salt Forms and Biological Activity of an Experimental
Antihypertensive", J. Pharm. Sci., 1972, pp. 1418-1422. cited by
examiner .
Kozma, David "Resolving Agents"., CRC Handbook of Optical
Resolutions via Diastereomeric Salt Formation, Chapter 4, CRC Press
LLC, Boca Raton, 2001, 47 pages. cited by applicant .
London et al., "Update and Review of Central Retinal Vein
Occlusion". Current Opinion in Ophthalmology, vol. 22, 2011, pp.
159-165. cited by applicant .
De Lucca et al., "Discovery and Structure-Activity Relationship of
N-(Ureidoalkyl)-Benzyl-Piperidines as Potent Small Molecule CC
Chemokine Receptor-3 (CCR3) Antagonists". Journal of Medicinal
Chemistry, vol. 45, 2002, pp. 3794-3804. cited by applicant .
Sato et al., "Synthesis and structure-activity relations of
N-{1-[(6-fluoro-2-naphthypmethyl]piperidin-4-yl}benzamide
derivatives as novel CCR3 antagonists". Bioorganic & Medicinal
Chemistry, vol. 16, 2008, pp. 144-156. cited by applicant .
Ting et al., "The synthesis of substituted bipiperidine amide
compounds as CCR3 antagonists". Bioorganic & Medicinal
Chemistry Letters, No. 15, 2005, pp. 1375-1378. cited by applicant
.
Wuts et al., "Protection for the Carboxyl Group". Greene's
Protective Groups in Organic Synthesis, Ch. 5, 4th Edition, NY
Wiley, 2007, pp. 553-559 and pp. 582-588. cited by applicant .
Bachert, C. et al., "Pharmacological Management of Nasal
Polyposis." Drugs, 2005, vol. 65, No. 11, pp. 1537-1552. cited by
applicant .
Blanchard, C. et al., "Eotaxin-3 and a Uniquely Conserved
Gene-Expression Profile in Eosinophilic Esophagitis." The Journal
of Clinical Investigation, 2006, vol. 116, No. 2, pp. 536-547.
cited by applicant .
International Search Report and Written Opinion for
PCT/EP2013/056867 dated Jun. 24, 2013. cited by applicant .
Takeda, A. et al., "CCR3 is a Target for Age-Related Macular
Degeneration Diagnosis and Therapy." Nature, 2009, vol. 460, No.
7252, pp. 225-230. cited by applicant .
London, Currrent Opinion in Opthamaology, "Update and Review of
Central Retinal Occlusion" 2011, p. 159-165. cited by applicant
.
Abstract in English of JP2006137718, 2006. cited by
applicant.
|
Primary Examiner: Hartley; Michael G.
Assistant Examiner: Rider; Lance W
Attorney, Agent or Firm: Foulds; Glenn J. Field; Bret E.
Bozicevic, Field & Francis LLP
Claims
What is claimed is:
1. A pharmaceutical composition comprising as an active ingredient
one or more compounds of formula 1 ##STR00014## wherein R.sup.1 is
H, C.sub.1-6-alkyl, C.sub.0-4-alkyl-C.sub.3-6-cycloalkyl, or
C.sub.1-6-haloalkyl; R.sup.2 is H, or C.sub.1-6-alkyl; X is
chloride; and j is 2, a first diluent that is dibasic calcium
phosphate anhydrous, a second diluent, a disintegrant, a lubricant
and optionally a binder, wherein the pharmaceutical composition
comprises TABLE-US-00021 10-90% active ingredient, 5-70% dibasic
calcium phosphate anhydrous, 5-30% second diluent, 0-30% binder,
1-12% disintegrant, and 0.1-3% lubricant.
2. The pharmaceutical composition of claim 1, wherein R.sup.1 is H
or Methyl; and R.sup.2 is H or Methyl.
3. The pharmaceutical composition according to claim 1, comprising
an additional disintegrant.
4. The pharmaceutical composition according to claim 1, comprising
a glidant.
5. The pharmaceutical composition according to claim 1, wherein the
lubricant is talc, polyethyleneglycol, calcium behenate, calcium
stearate, hydrogenated castor oil or magnesium stearate.
6. The pharmaceutical composition according to claim 1, wherein the
binder is copovidone (copolymerisates of vinylpyrrolidon with other
vinylderivates), hydroxypropyl methylcellulose (HPMC),
hydroxypropylcellulose (HPC) or polyvinylpyrrolidon (Povidone).
7. The pharmaceutical composition according to claim 1, wherein the
disintegrant is crosscarmelose sodium.
8. The pharmaceutical composition according to claim 4, wherein the
glidant is colloidal silicon dioxide.
9. The pharmaceutical composition according to claim 3, wherein the
additional disintegrant is crospovidone.
10. The pharmaceutical composition according to claim 1 in the
dosage form of a capsule, a tablet or a film-coated tablet.
11. The pharmaceutical composition of claim 10, comprising 2-4%
film coat.
12. The pharmaceutical composition according to claim 11, wherein
the film coat comprises a film-forming agent, a plasticizer, a
glidant and optionally one or more pigments.
13. The pharmaceutical composition of claim 12, wherein the film
coat comprises Polyvinyl alcohol (PVA) or
hydroxypropylmethylcellulose (HPMC), polyethylene glycol (PEG),
talc, titanium dioxide and iron oxide.
14. A pharmaceutical composition comprising as an active ingredient
one or more compounds of formula 1 ##STR00015## wherein R.sup.1 is
methyl; R.sup.2 is methyl; X is chloride; and j is 2, a first
diluent that is dibasic calcium phosphate anhydrous, a second
diluent, a disintegrant, a lubricant and optionally a binder,
wherein the pharmaceutical composition comprises TABLE-US-00022
10-90% active ingredient; 5-70% dibasic calcium phosphate
anhydrous; 5-30% second diluent; 0-30% binder; 1-12% disintegrant;
and 0.1-3% lubricant.
15. The pharmaceutical composition according to claim 14, wherein
the lubricant is talc, polyethyleneglycol, calcium behenate,
calcium stearate, hydrogenated castor oil or magnesium
stearate.
16. The pharmaceutical composition according to claim 14, wherein
the binder is copovidone (copolymerisates of vinylpyrrolidon with
other vinylderivates), hydroxypropyl methylcellulose (HPMC),
hydroxypropylcellulose (HPC) or polyvinylpyrrolidon (Povidone).
17. The pharmaceutical composition according to claim 14, wherein
the disintegrant is crosscarmelose sodium.
Description
The present invention relates to pharmaceutical compositions
containing one or more compounds of formula 1
##STR00002## wherein R.sup.1 is H, C.sub.1-6-alkyl,
C.sub.0-4-alkyl-C.sub.3-6-cycloalkyl, C.sub.1-6-haloalkyl; R.sup.2
is H, C.sub.1-6-alkyl; X is an anion selected from the group
consisting of chloride or 1/2 dibenzoyltartrate j is 1 or 2.
processes for the preparation thereof, and their use to treat
diseases connected with the CCR3 receptor
BACKGROUND OF THE INVENTION
Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa,
that are released by a wide variety of cells to attract and
activate, among other cell types, macrophages, T and B lymphocytes,
eosinophils, basophils and neutrophils (reviewed in Luster, New
Eng. J. Med., 338, 436-445 (1998); Rollins, Blood, 90, 909-928
(1997); Lloyd, Curr. Opin. Pharmacol., 3, 443-448 (2003); Murray,
Current Drug Targets., 7, 579-588 (2006); Smit, Eur J. Pharmacol.,
533, 277-88 (2006)
There are two major classes of chemokines, CXC and CC, depending on
whether the first two cysteines in the amino acid sequence are
separated by a single amino acid (CXC) or are adjacent (CC). The
CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating
protein-2 (NAP2) and melanoma growth stimulatory activity protein
(MGSA) are chemotactic primarily for neutrophils and T lymphocytes,
whereas the CC chemokines, such as RANTES, MIP-1a, MIP-1, the
monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and
MCP-5) and the eotaxins (-1, -2, and -3) are chemotactic for, among
other cell types, macrophages, T lymphocytes, eosinophils, mast
cells, dendritic cells, and basophils. Also in existence are the
chemokines lymphotactin-1, lymphotactin-2 (both C chemokines), and
fractalkine (a CXXXC chemokine) that do not fall into either of the
major chemokine subfamilies.
The chemokines bind to specific cell-surface receptors belonging to
the family of G-protein-coupled seventransmembrane-domain proteins
(reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994); Murphy,
Pharmacol Rev., 54 (2):227-229 (2002); Allen, Annu. Rev. Immunol.,
25, 787-820 (2007)) which are termed "chemokine receptors." On
binding their cognate ligands, chemokine receptors transduce an
intracellular signal through the associated trimeric G proteins,
resulting in, among other responses, a rapid increase in
intracellular calcium concentration, activation of G-proteins,
changes in cell shape, increased expression of cellular adhesion
molecules, degranulation, promotion of cell migration, survival and
proliferation. There are at least eleven human chemokine receptors
that bind or respond to CC chemokines with the following
characteristic patterns: CCR-1 (or "CKR-1" or "CC-CKR-1") [MIP-1a,
MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell, 72, 415-425
(1993), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-2A and
CCR-2B (or "CKR-2A"/"CKR-2B" or "CC-CKR-2A"/"CC-CKR-2B") [MCP-1,
MCP2, MCP-3, MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad. Sci.
USA, 91, 2752-2756 (1994), Luster, New Eng. J. Med., 338, 436-445
(1998)); CCR3 (or "CKR-3" or "CC-CKR-3") [eotaxin-1, eotaxin-2,
RANTES, MCP-3, MCP-4] (Combadiere, et al., J. Biol. Chem., 270,
16491-16494 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998));
CCR-4 (or "CKR-4" or "CC-CKR-4") [TARC, MIP-1a, RANTES, MCP-1]
(Power et al., J. Biol. Chem., 270, 19495-19500 (1995), Luster, New
Eng. J. Med., 338, 436-445 (1998)); CCR-5 (or "CKR-5" OR "CCCKR-5")
[MIP-1a, RANTES, MIP-1p] (Sanson, et al., Biochemistry, 35,
3362-3367 (1996)); CCR-6 (or "CKR-6" or "CC-CKR-6") [LARC] (Baba et
al., J. Biol. Chem., 272, 14893-14898 (1997)); CCR-7 (or "CKR-7" or
"CC-CKR-7") [ELC] (Yoshie et al., J. Leukoc. Biol. 62, 634-644
(1997)); CCR-8 (or "CKR-8" or "CC-CKR-8") [1-309, TARC, MIP-1p]
(Napolitano et al., J. Immunol., 157, 2759-2763 (1996), Bernardini
et al., Eur. J. Immunol., 28, 582-588 (1998)); CCR-10 (or "CKR-10"
or "CC-CKR-10") [MCP-1, MCP-3] (Bonini et al, DNA and Cell Biol.,
16, 1249-1256 (1997)); and CCR31 (or "CKR-11" or "CC-CKR-11")
[MCP-1, MCP-2, MCP-4](Schweickart et al., J Biol Chem, 275
9550-9556 (2000)).
In addition to the mammalian chemokine receptors, the Decoy
receptors CCX-CKR, D6 and DARC/Duffy as well as proteins expressed
by mammalian cytomegaloviruses, herpes viruses and poxviruses,
exhibit binding properties of chemokine receptors (reviewed by
Wells and Schwartz, Curr. Opin. Biotech., 8, 741-748 (1997);
Comerford, Bioessays., 29(3):237-47 (2007)). Human CC chemokines,
such as RANTES and MCP-3, can cause rapid mobilization of calcium
via these virally encoded receptors. Receptor expression may be
permissive for infection by allowing for the subversion of normal
immune system surveillance and response to infection. Additionally,
human chemokine receptors, such as CXCR-4, CCR2, CCR3, CCR5 and
CCR8, can act as co receptors for the infection of mammalian cells
by microbes as with, for example, the human immunodeficiency
viruses (HIV).
Chemokine receptors have been implicated as being important
mediators of inflammatory, infectious, and immunoregulatory
disorders and diseases, including asthma and allergic diseases, as
well as autoimmune pathologies such as rheumatoid arthritis,
Grave's disease, chronic obstructive pulmonary disease, and
atherosclerosis. For example, the chemokine receptor CCR3 is
expressed among others on eosinophils, basophils, TH2 cells,
alveolar macrophages, mast cells, epithelial cells, microglia
cells, astrocytes and fibroblasts. CCR3 plays a pivotal role in
attracting eosinophils to sites of allergic inflammation and in
subsequently activating these cells. The chemokine ligands for CCR3
induce a rapid increase in intracellular calcium concentration,
increased GTP exchange of G-proteins, increased ERK
phosphorylation, enhanced receptor internalization, eosinophil
shape change, increased expression of cellular adhesion molecules,
cellular degranulation, and the promotion of migration.
Accordingly, agents that inhibit chemokine receptors would be
useful in such disorders and diseases. In addition, agents that
inhibit chemokine receptors would also be useful in infectious
diseases, e.g., by blocking infection of CCR3 expressing cells by
HIV or in preventing the manipulation of immune cellular responses
by viruses such as cytomegaloviruses.
Therefore, CCR3 is an important target and antagonism of CCR3 is
likely to be effective in the treatment of inflammatory,
eosinophilic, immunoregulatory and infectious disorders and
diseases (Wegmann, Am J Respir Cell Mol. Biol., 36(1):61-67 (2007);
Fryer J Clin Invest., 116(1):228-236 (2006); De Lucca, Curr Opin
Drug Discov Devel., 9(4):516-524 (2006)
It has been found and disclosed in WO 2010 115836 that the
substituted piperidines of formula 1 are highly suitable as CCR3
antagonists, having less side effects, e.g., inhibition of
norepinephrine (NET), dopamine (DAT) or serotonin reuptake
transporters (5-HTT) as described by Watson P S, Bioorg Med Chem.
Lett., 16(21):5695-5699 (2006), or inhibition of 5HT2A, 5HT2C or
Dopamine D2 receptors as described by De Lucca, J Med. Chem.,
48(6):2194-2211 (2005), or inhibition of the hERG channel as
described by De Lucca, Curr Opin Drug Discov Devel., 9(4):516-524
(2006), or inhibition of the alpha1B adrenergic receptor.
Thus, these compounds of formula 1 could be used as a medicament in
pharmaceutical formulations similar to those known from the prior
art (List et al., Arzneiformen-lehre, Wissenschaftliche
Verlagsgesellschaft mbH Stuttgart, 4.Auflage, p70ff)
From initial stability experiments with the compounds it became
apparent, that the drug substance will require stabilizing effects
due to the manufacturing process and/or the formulation ingredients
to enable sufficient stability under standard conditions for
medicaments according to the regulations of Drug Registration
Authorities. In addition widely used standard manufacturing
processes like direct compression or aqueous granulation could not
be applied to the compound, due to the physical characteristics of
the drug substance such as bulk density or deriving Hausner factor,
electrostatic charging and surface adhesive properties. These
characteristics may significantly influence key features such as
flowability and compressibility, which are important for processing
of the drug substance in order to manufacture a pharmaceutical
dosage form.
TABLE-US-00001 TABLE 1 Hausner Factor and corresponding Flow
Properties Hausner Factor Flow Properties 1.05-1.18 Excellent
1.14-1.19 Good 1.22-1.27 Acceptable 1.30-1.54 Bad 1.49-1.61 Very
bad >1.67 No flow
The Hausner factor is the ratio of bulk volume to compacted volume,
calculated by the formula bulk density/tapped density. Bulk density
is measured according to Ph. Eur. 2.9.15 (European Pharmacopoeia,
4. Ed.) as poured density. The tapped density is measured according
to Ph. Eur. 2.9.15 (see also Voigt R., Lehrbuch der
pharmazeutischen Technologie [Textbook of Pharmaceutical
Technology], Verlag Chemie, 5th Edition, page 148). The Hausner
factor is a measure for the flowability/compressibility of powders
and ideally should be close to 1.
Thus, the skilled artisan would have expected the need to find a
new and inventive pharmaceutical formulation for compounds of
formula 1, to prevent the drug substance in the formulation from
degradation, especially hydrolytical cleavage which can be caused
by air moisture and the water content of standard pharmaceutical
excipients.
DETAILED DESCRIPTION OF THE INVENTION
A first object of the present invention is a pharmaceutical
composition containing one or more compounds of formula 1
##STR00003## wherein R.sup.1 is H, C.sub.1-6-alkyl,
C.sub.0-4-alkyl-C.sub.3-6-cycloalkyl, C.sub.1-6-haloalkyl; R.sup.2
is H, C.sub.1-6-alkyl; X is an anion selected from the group
consisting of chloride or 1/2 dibenzoyltartrate j is 1 or 2;
processes for the preparation thereof, and their use to treat
diseases connected with the CCR3 receptor
Preferred is a pharmaceutical composition containing one or more
compounds of formula 1 wherein R.sup.1 is H, C.sub.1-6-alkyl;
R.sup.2 is H, C.sub.1-6-alkyl; X is an anion selected from the
group consisting of chloride or 1/2 dibenzoyltartrate j is 1 or
2.
Preferred is a pharmaceutical composition containing one or more
compounds of formula 1 wherein R.sup.1 is H, Methyl, Ethyl, Propyl,
Butyl; R.sup.2 is H, Methyl, Ethyl, Propyl, Butyl; X is an anion
selected from the group consisting of chloride or 1/2
dibenzoyltartrate, preferably chloride; j is 1 or 2, preferably
2.
Preferred is a pharmaceutical composition containing one or more
compounds of formula 1 wherein R.sup.1 is H, Methyl, Ethyl, Propyl,
Butyl; R.sup.2 is H, Methyl; X is an anion selected from the group
consisting of chloride or 1/2 dibenzoyltartrate, preferably
chloride; j is 1 or 2, preferably 2.
Preferred is a pharmaceutical composition containing one or more
compounds of formula 1 wherein R.sup.1 is H, Methyl; R.sup.2 is H,
Methyl; X is an anion selected from the group consisting of
chloride or 1/2 dibenzoyltartrate, preferably chloride; j is 1 or
2, preferably 2.
Preferred is a pharmaceutical composition containing one or more of
the examples 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 according to the table
below as a hydrochloride. Furthermore preferred is a pharmaceutical
composition containing one or more of the examples 1, 2, 3, 4, 5,
6, 7, 8, 9 or 10 according to the table below as a
di-hydrochloride.
Another object of the present invention is the above pharmaceutical
dosage form, wherein it is an orally deliverable dosage form.
Another object of the present invention is the above pharmaceutical
dosage form which is in the form of a tablet (including a film
coated tablet), capsule, pellets, powder or granules.
Another object of the present invention is the above pharmaceutical
dosage form for use as medicament.
Another object of the present invention is the above pharmaceutical
dosage form for the treatment of a disease or condition selected
from respiratory diseases.
Another object of the present invention is the use of the above
pharmaceutical dosage form for the preparation of a medicament for
the treatment of a disease or condition selected from respiratory
diseases.
Another object of the present invention is a process for the
treatment and/or prevention of a disease or condition selected from
respiratory diseases, characterized in that an effective amount of
the above defined pharmaceutical dosage form is administered orally
to a patient once, twice, thrice or several times daily.
USED TERMS AND DEFINITIONS
The term "about" means 5% more or less of the specified value.
Thus, about 100 minutes could also be read as from 95 to 105
minutes.
Terms not specifically defined herein should be given the meanings
that would be given to them by one of skill in the art in light of
the disclosure and the context. As used in the specification,
however, unless specified to the contrary, the following terms have
the meaning indicated and the following conventions are adhered
to.
In the groups, radicals, or moieties defined below, the number of
carbon atoms is often specified preceding the group, for example,
C.sub.1-6-alkyl means an alkyl group or radical having 1 to 6
carbon atoms. In general, for groups comprising two or more
subgroups, the first named subgroup is the radical attachment
point, for example, the substituent "C.sub.1-3-alkyl-aryl" means an
aryl group which is bound to a C.sub.1-3-alkyl-group, the latter of
which is bound to the core or to the group to which the substituent
is attached.
In case a compound of the present invention is depicted in form of
a chemical name and also as a formula, in any discrepancy between
the two descriptions of the compound the formula shall prevail. An
asterisk is may be used in sub-formulas to indicate the bond which
is connected to the core molecule as defined.
Unless specifically indicated, throughout the specification and the
appended claims, a given chemical formula or name shall encompass
tautomers and all stereo, optical and geometrical isomers (e.g.
enantiomers, diastereomers, E/Z isomers etc. . . . ) and racemates
thereof as well as mixtures in different proportions of the
separate enantiomers, mixtures of diastereomers, or mixtures of any
of the foregoing forms where such isomers and enantiomers exist, as
well as salts, including pharmaceutically acceptable salts thereof
and solvates thereof such as for instance hydrates including
solvates of the free compounds or solvates of a salt of the
compound.
The term "C.sub.1-n-alkyl", wherein n is an integer from 2 to n,
either alone or in combination with another radical denotes an
acyclic, saturated, branched or linear hydrocarbon radical with 1
to n C atoms. For example the term C.sub.1-5-alkyl embraces the
radicals H.sub.3C--, H.sub.3C--CH.sub.2--,
H.sub.3C--CH.sub.2--CH.sub.2--, H.sub.3C--CH(CH.sub.3)--,
H.sub.3C--CH.sub.2--CH.sub.2--CH.sub.2--,
H.sub.3C--CH.sub.2--CH(CH.sub.3)--,
H.sub.3C--CH(CH.sub.3)--CH.sub.2--, H.sub.3C--C(CH.sub.3).sub.2--,
H.sub.3C--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
H.sub.3C--CH.sub.2--CH.sub.2--CH(CH.sub.3)--,
H.sub.3C--CH.sub.2--CH(CH.sub.3)--CH.sub.2--,
H.sub.3C--CH(CH.sub.3)--CH.sub.2--CH.sub.2--,
H.sub.3C--CH.sub.2--C(CH.sub.3).sub.2--,
H.sub.3C--C(CH.sub.3).sub.2--CH.sub.2--,
H.sub.3C--CH(CH.sub.3)--CH(CH.sub.3- and
H.sub.3C--CH.sub.2--CH(CH.sub.2CH.sub.3-.
The term "C.sub.1-n-haloalkyl", wherein n is an integer from 2 to
n, either alone or in combination with another radical denotes an
acyclic, saturated, branched or linear hydrocarbon radical with 1
to n C atoms wherein one or more hydrogen atoms are replaced by a
halogene atom selected from among fluorine, chlorine or bromine,
preferably fluorine and chlorine, particularly preferably fluorine.
Examples include: CH.sub.2F, CHF.sub.2, CF.sub.3.
The term "C.sub.3-n-cycloalkyl", wherein n is an integer from 4 to
n, either alone or in combination with another radical denotes a
cyclic, saturated, unbranched hydrocarbon radical with 3 to n C
atoms. For example the term C.sub.3-7-cycloalkyl includes
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl.
Dosage Forms/Ingredients
Solid pharmaceutical compositions ready for use/ingestion made from
a compound of formula 1 comprise powders, granules, pellets,
tablets, capsules, chewable tablets, dispersible tables, troches
and lozenges. In detail: Capsule formulations according to the
invention comprise the powdery intermediate of a compound of
formula 1, an intermediate blend comprising the powdery
intermediate, pellets or granules obtained by conventional wet-,
dry or hot-melt granulation or hot-melt extrusion or spray-drying
of a suitable intermediate blend, filled in conventional capsules,
e.g., hard gelatin or HPMC capsules. The Capsule formulations from
above may also comprise the powdery intermediate of a compound of
formula 1 in a compacted form. Capsule formulations according to
the invention comprise the compound of formula 1 suspended or
diluted in a liquid or mixture of liquids. Tablet formulations
according to the invention comprise such tablets obtained by direct
compression of a suitable final blend or by tableting of pellets or
granules obtained by conventional wet-, dry or hot-melt granulation
or hot-melt extrusion or spray-drying of a suitable intermediate
blend.
Another object of the present invention is a dosage form where a
pH-adjusting or buffering agent is added for stability improvement
of the active ingredient. The pH-adjusting/buffering agent may be a
basic amino acid, which has an amino group and alkaline
characteristics (isoelectric point, pI: 7.59-10.76), such as e.g.
L-arginine, L-lysine or L-histidine. The pH-adjusting/buffering
agent may also be a basic sugar alcohol, like meglumine A preferred
pH-adjusting agent within the meaning of this invention is meglumin
or L-arginine. L-arginine and meglumine have a particular suitable
stabilizing effect on the compositions of this invention, e.g. by
suppressing chemical degradation of compounds of formula 1.
Thus, in an embodiment, the present invention is directed to a
pharmaceutical composition (e.g. an oral solid dosage form,
particularly a tablet) comprising a compound of formula 1 and
L-arginine or meglumine for stabilizing the composition,
particularly against chemical degradation; as well as one or more
pharmaceutical excipients.
Suitably the pharmaceutical excipients used within this invention
are conventional materials such as cellulose and its derivates,
D-mannitol, dibasic calcium phosphate, corn starch, pregelatinized
starch as a filler, copovidone as a binder, crospovidone as
disintegrant, magnesium stearate as a lubricant, colloidal
anhydrous silica as a glidant, hypromellose, polyvinyl alcohol as
film-coating agents, polyethylene glycol as a plasticizer, titanium
dioxide, iron oxide red/yellow as a pigment, and talc, etc.
In detail pharmaceutical excipients can be a first and second
diluent, a binder, a disintegrant and a lubricant; an additional
disintegrant and an additional glidant are a further option.
Diluents suitable for a pharmaceutical composition according to the
invention are cellulose powder, microcrystalline cellulose, lactose
in various crystalline modifications, dibasic calciumphosphate
anhydrous, dibasic calciumphosphate dihydrate, erythritol, low
substituted hydroxypropyl cellulose, mannitol, starch or modified
starch (e.g., pregelatinized or partially hydrolysed) or xylitol.
Among those diluents dibasic calciumphosphate anhydrous and
microcrystalline cellulose are preferred. Diluents preferred as the
second diluent are the above mentioned diluents dibasic
calciumphosphate anhydrous and microcrystalline cellulose.
Lubricants suitable for a pharmaceutical composition according to
the invention are talc, polyethyleneglycol, calcium behenate,
calcium stearate, sodium stearylfumarate, hydrogenated castor oil
or magnesium stearate. The preferred lubricant is magnesium
stearate. Binders suitable for a pharmaceutical composition
according to the invention are copovidone (copolymerisates of
vinylpyrrolidon with other vinylderivates), hydroxypropyl
methylcellulose (HPMC), hydroxypropylcellulose (HPC),
polyvinylpyrrolidon (povidone), pregelatinized starch,
stearic-palmitic acid, low-substituted hydroxypropylcellulose
(L-HPC), copovidone and pregelatinized starch being preferred. The
above mentioned binders pregelatinized starch and L-HPC show
additional diluent and disintegrant properties and can also be used
as the second diluent or the disintegrant. Disintegrants suitable
for a pharmaceutical composition according to the present invention
are corn starch, crospovidone, polacrilin potassium, croscarmellose
sodium, low-substituted hydroxypropylcellulose (L-HPC) or
pregelatinized starch; preferably croscarmellose sodium. As an
optional glidant colloidal silicon dioxide can be used.
An exemplary composition according to the present invention
comprises the diluent dibasic calciumphosphate, microcrystalline
cellulose as a diluent with additional disintegrating properties,
the binder copovidone, the disintegrant croscarmellose sodium, and
magnesium stearate as the lubricant.
Typical pharmaceutical compositions comprise (% by weight)
TABLE-US-00002 10-50% active ingredient 20-88% diluent 1, 5-50%
diluent 2, 1-5% binder, 1-15% disintegrant, and 0.1-5%
lubricant.
Preferred pharmaceutical compositions comprise (% by weight)
TABLE-US-00003 10-50% active ingredient 20-75% diluent 1, 5-30%
diluent 2, 2-30% binder, 1-12% disintegrant, and 0.1-3%
lubricant
Preferred pharmaceutical compositions comprise (% by weight)
TABLE-US-00004 10-90% active ingredient 5-70% diluent 1, 5-30%
diluent 2, 0-30% binder, 1-12% disintegrant, and 0.1-3%
lubricant
Preferred pharmaceutical compositions comprise (% by weight)
TABLE-US-00005 10-50% active ingredient 20-75% diluent 1, 5-30%
diluent 2, 2-30% binder, 0.5-20% buffering agent, 1-12%
disintegrant, and 0.1-3% lubricant
Preferred pharmaceutical compositions comprise (% by weight)
TABLE-US-00006 30-70% active ingredient 20-75% diluent 1, 5-30%
diluent 2, 2-30% binder, 0.5-20% buffering agent, 1-12%
disintegrant, and 0.1-3% lubricant
Preferred pharmaceutical compositions comprise (% by weight)
TABLE-US-00007 30-70% active ingredient 10-75% diluent 1, 5-30%
diluent 2, 0-30% binder, 0.5-30% buffering agent, 1-12%
disintegrant, and 0.1-3% lubricant
Preferred pharmaceutical compositions comprise (% by weight)
TABLE-US-00008 30-70% active ingredient 10-75% diluent 1, 5-30%
diluent 2, 0.5-30% buffering agent, 1-12% disintegrant, and 0.1-3%
lubricant
Pharmaceutical compositions containing 10-90% of active ingredient,
preferably 30-70% active ingredient (% by weight) are
preferred.
A tablet formulation according to the invention may be uncoated or
coated, e.g. film-coated, using suitable coatings known not to
negatively affect the dissolution properties of the final
formulation. For instance the tablets can be provided with a seal
coat for protection of the patients' environment and clinical staff
as well as for moisture protection purposes by dissolving a high
molecular weight polymer as polyvinylpyrrolidone or polyvinyl
alcohol or hydroxypropyl-methylcellulose together with
plasticizers, lubricants and optionally pigments and tensides in
water or organic solvent as acetone and spraying this mixture on
the tablet cores inside a coating equipment as a pan coater or a
fluidized bed coater with wurster insert.
Additionally, agents such as beeswax, shellac, cellulose acetate
phthalate, polyvinyl acetate phthalate, and film forming polymers
such as hydroxypropyl cellulose, ethylcellulose and polymeric
methacrylates can be applied to the tablets, provided that the
coating has no substantial effect on the disintegration/dissolution
of the dosage form and that the coated dosage form is not affected
in its stability.
After the dosage form is film-coated, a sugar coating may be
applied onto the sealed pharmaceutical dosage form. The sugar
coating may comprise sucrose, dextrose, sorbitol and the like or
mixtures thereof. If desired, colorants or opacifiers may be added
to the sugar solution.
Solid formulations of the present invention tend to be hygroscopic.
They may be packaged using PVC-blisters, PVDC-blisters or a
moisture-proof packaging material such as aluminum foil blister
packs, alu/alu blister, transparent or opaque polymer blister with
pouch, polypropylene tubes, glass bottles and HDPE bottles
optionally containing a child-resistant feature or may be tamper
evident. The primary packaging material may comprise a desiccant
such as molecular sieve or silica gel to improve chemical stability
of the active ingredient. Opaque packaging such as colored blister
materials, tubes, brown glass bottles or the like can be used to
prolong shelf life of the active ingredient by reduction of photo
degradation.
Dosages
A dosage range of the compound of formula 1 is usually between 100
and 1000 mg, in particular between 200 and 900 mg, 300 and 900 mg
or 350 and 850 mg or 390 and 810 mg. It is possible to give one or
two tablets, preferred are two tablets for a daily oral dosage of
100, 200, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800,
850, 900 mg, preferably 350, 400, 450, 750, 800, 850.
The dosages range can be achieved by one tablet or by two tablets;
preferably two tablets are administered, each containing half of
the dosage.
The application of the active ingredient may occur up to three
times a day, preferably one or two times a day. Particular dosage
strengths are 400 mg or 800 mg.
Methods of Production
Direct Compression
Due to the bad flowability properties of the drug substance and the
high Hausner factor of approx 1.40 a direct compression process to
produce tablets is not feasible. Therefore a granulation process
(wet or dry granulation) has to be performed.
Wet Granulation
In the wet granulation process the granulation liquid is a solvent
such as water, ethanol, methanol, isopropanol, acetone, preferably
ethanol, and contains a binder such as copovidone. The solvent is a
volatile component, which does not remain in the final product. The
active ingredient and the other excipients with exception of the
lubricant are premixed and granulated with the granulation liquid
using a high shear granulator. The wet granulation step is followed
by an optional wet sieving step, drying and dry sieving of the
granules. For example a fluid bed dryer can then be used for
drying.
The dried granules are sieved through an appropriate sieve. After
addition of the other excipients with exception of the lubricant
the mixture is blended in a suitable conventional blender such as a
free fall blender followed by addition of the lubricant such as
magnesium stearate and final blending in the blender.
Thus an exemplary wet granulation process for the preparation of a
pharmaceutical composition according to the present invention
comprises a. dissolving a binder such as copovidone in a solvent
such as ethanol at ambient temperature to produce a granulation
liquid; b. blending a compound of formula 1, a diluent, and a
disintegrant in a suitable mixer, to produce a pre-mix; c.
moistening the pre-mix with the granulation liquid and subsequently
granulating the moistened pre-mix for example in a high shear
mixer; d. optionally sieving the granulated pre-mix through a sieve
with a mesh size of at least 1.0 mm and preferably 3 mm; e. drying
the granulate at about 40-75.degree. C. and preferably
55-65.degree. C. inlet air temperature for example in a fluid bed
dryer until the desired loss on drying value in the range of 1-3%
is obtained; f. delumping the dried granulate for example by
sieving through a sieve with a mesh size of 0.6 mm-1.6 mm,
preferably 1.0 mm; and g. adding preferably sieved lubricant to the
granulate for final blending for example in a cube mixer.
In an alternative process part of the excipients such as part of a
disintegrant (e.g., corn starch) or a diluent (e.g., pregelatinized
starch) or an additional disintegrant (crospovidone) can be added
extragranular prior to final blending of step g.
In another alternative version of the process, the granulate
produced in steps a to e is produced in a one pot high shear
granulation process and subsequent drying in a one pot
granulator.
For the preparation of capsules the final blend is further filled
into capsules.
For the preparation of tablets or tablet cores, the final blend is
further compressed into tablets of the target tablet core weight
with appropriate size and crushing strength, using an appropriate
tablet press.
For the preparation of film-coated tablets a coating suspension is
prepared and the compressed tablet cores are coated with the
coating suspension to a weight gain of about 2-4%, preferably about
3%, using a standard film coater. The film-coating solvent is a
volatile component, which does not remain in the final product. To
reduce the required amount of lubricant in the tablets it is an
option to use an external lubrication system.
Fluid Bed Granulation
In the wet granulation process the granulation liquid is a solvent
such as water, ethanol, methanol, isopropanol, acetone, preferably
ethanol, and contains a binder such as copovidone. The solvent is a
volatile component, which does not remain in the final product. The
active ingredient and the other excipients with exception of the
lubricant are premixed and granulated with the granulation liquid
using a fluid bed granulator. The granulation step is followed by a
dry sieving of the granules.
The dried granules are sieved through an appropriate sieve. After
addition of the other excipients with exception of the lubricant
the mixture is blended in a suitable conventional blender such as a
free fall blender followed by addition of the lubricant such as
magnesium stearate and final blending in the blender.
Thus an exemplary wet granulation process for the preparation of a
pharmaceutical composition according to the present invention
comprises a. dissolving a binder such as copovidone in a solvent
such as purified water at ambient temperature to produce a
granulation liquid; b. blending a compound of formula 1, a diluent,
and a disintegrant in the fluid bed, to produce a pre-mix; c.
granulate the pre-mix with the granulation liquid in a fluid bed
granulator; d. performing the drying step of the granulate at about
40-75.degree. C. and preferably 55-65.degree. C. inlet air until
the desired loss on drying value in the range of 1-3% is obtained;
e. delumping the dried granulate for example by sieving through a
sieve with a mesh size of 0.6 mm-1.6 mm, preferably 1.0 mm; and f.
adding preferably sieved lubricant to the granulate for final
blending for example in a cube mixer.
In an alternative process part of the excipients such as part of a
disintegrant (e.g., corn starch) or a diluent (e.g., pregelatinized
starch) or an additional disintegrant (crospovidone) can be added
extragranular prior to final blending of step f.
For the preparation of capsules the final blend is further filled
into capsules.
For the preparation of tablets or tablet cores the final blend is
further compressed into tablets of the target tablet core weight
with appropriate size and crushing strength, using an appropriate
tablet press.
For the preparation of film-coated tablets a coating suspension is
prepared and the compressed tablet cores are coated with the
coating suspension to a weight gain of about 2-4%, preferably about
3%, using a standard film coater. The film-coating solvent is a
volatile component, which does not remain in the final product. To
reduce the required amount of lubricant in the tablets it is an
option to use an external lubrication system.
Hot Melt Granulation
In the hot melt granulation process the binder is a melting agent
such as polyethylene glycol, stearic acid, stearic-palmitic acid,
poloxamer, glyceryl monostearate or polyethylene oxide. The active
ingredient and the other excipients with exception of the lubricant
are premixed and granulated with the binder using for example a
high shear granulator. The granulation step is followed by a
cooling step, and sieving of the granules.
The granules are sieved through an appropriate sieve. After
addition of the other excipients with exception of the lubricant
the mixture is blended in a suitable conventional blender such as a
free fall blender followed by addition of the lubricant such as
magnesium stearate and final blending in the blender.
Thus an exemplary hot melt granulation process for the preparation
of a pharmaceutical composition according to the present invention
comprises a. blending a compound of formula 1, a diluent, and a
disintegrant in a suitable mixer, to produce a pre-mix; b. heating
the pre-mix and subsequently granulating the pre-mix for example in
a high shear mixer; c. cooling down the granulate at approx
28.degree. d. delumping the granulate for example by sieving
through a sieve with a mesh size of 0.6 mm-1.6 mm, preferably 1.0
mm; and e. adding preferably sieved lubricant to the granulate for
final blending for example in a cube mixer.
In an alternative process part of the excipients such as part of a
disintegrant (e.g., corn starch) or a diluent (e.g. pregelatinized
starch) or an additional disintegrant (crospovidone) can be added
extragranular prior to final blending of step e.
In another alternative version of the process the granulate
produced in steps a to c is produced in a one pot high shear
granulation.
For the preparation of capsules the final blend is further filled
into capsules.
For the preparation of tablets or tablet cores the final blend is
further compressed into tablets of the target tablet core weight
with appropriate size and crushing strength, using an appropriate
tablet press.
For the preparation of film-coated tablets a coating suspension is
prepared and the compressed tablet cores are coated with the
coating suspension to a weight gain of about 2-4%, preferably about
3%, using a standard film coater. The film-coating solvent is a
volatile component, which does not remain in the final product. To
reduce the required amount of lubricant in the tablets it is an
option to use an external lubrication system.
Roller Compaction
In the dry granulation process the active ingredient alone or the
active ingredient together with the lubricant or the active
ingredient and the diluent or a mixture of the diluent and the
lubricant are premixed and compacted using a roller compactor. The
dry granulation step is followed by one or two sieving steps.
The granules are sieved through an appropriate sieve. After
addition of the other excipients with exception of the lubricant
the mixture is blended in a suitable conventional blender such as a
free fall blender followed by addition of the lubricant such as
magnesium stearate and final blending in the blender.
Thus an exemplary dry granulation process for the preparation of a
pharmaceutical composition according to the present invention
comprises a. blending a compound of formula 1, a diluent, and a
lubricant in a suitable mixer, to produce a pre-mix; b. compacting
the pre-mix using a roller compactor c. sieving the granulated
pre-mix through a sieve with a mesh size of at least 0.6 mm and
preferably 0.8 mm; d. delumping the granulate for example by
sieving through a sieve with a mesh size of 0.6 mm-1.6 mm,
preferably 1.0 mm; and e. adding additional diluent and
disintegrant and blend in a suitable blender f. adding preferably
sieved lubricant to the granulate for final blending for example in
a cube mixer.
In an alternative process part of the excipients such as part of a
disintegrant or a binder (copovidone) can be added intragranular
prior to granulation of step b.
For the preparation of capsules the final blend is further filled
into capsules.
For the preparation of tablets or tablet cores the final blend is
further compressed into tablets of the target tablet core weight
with appropriate size and crushing strength, using an appropriate
tablet press.
For the preparation of film-coated tablets a coating suspension is
prepared and the compressed tablet cores are coated with the
coating suspension to a weight gain of about 2-4%, preferably about
3%, using a standard film coater. The film-coating solvent is a
volatile component, which does not remain in the final product. To
reduce the required amount of lubricant in the tablets it is an
option to use an external lubrication system.
Hot Melt Extrusion
In the hot melt extrusion process the binder is a melting agent
such as polyethylene glycol, stearic acid, stearic-palmitic acid,
poloxamer, vitamin E TGPS, glyceryl monostearate or polyethylene
oxide. The active ingredient and the other excipients with
exception of the lubricant are premixed and granulated with the
binder using an extruder. The granulation step is followed by a
cooling step, and sieving of the granules.
The granules are sieved through an appropriate sieve. After
addition of the other excipients with exception of the lubricant
the mixture is blended in a suitable conventional blender such as a
free fall blender followed by addition of the lubricant such as
magnesium stearate and final blending in the blender.
Thus an exemplary hot melt extrusion process for the preparation of
a pharmaceutical composition according to the present invention
comprises a. blending a compound of formula 1 and a binder in a
suitable mixer, to produce a pre-mix; b. granulating the heated
pre-mix in an extruder; c. optionally sieving the granulated
pre-mix through a sieve with a mesh size of at least 1.0 mm and
preferably 3 mm; d. delumping the granulate for example by sieving
through a sieve with a mesh size of 0.6 mm-1.6 mm, preferably 1.0
mm; e. and adding a diluent and a disintegrant and blending in a
suitable blender f. adding preferably sieved lubricant to the
granulate for final blending for example in a cube mixer.
In an alternative process part of the excipients such as part of a
disintegrant or a diluent or an additional disintegrant can be
added intragranular prior to extrusion of step b.
For the preparation of capsules the final blend is further filled
into capsules.
For the preparation of tablets or tablet cores the final blend is
further compressed into tablets of the target tablet core weight
with appropriate size and crushing strength, using an appropriate
tablet press.
For the preparation of film-coated tablets a coating suspension is
prepared and the compressed tablet cores are coated with the
coating suspension to a weight gain of about 2-4%, preferably about
3%, using a standard film coater. The film-coating solvent is a
volatile component, which does not remain in the final product. To
reduce the required amount of lubricant in the tablets it is an
option to use an external lubrication system.
EXAMPLES
The present invention is directed to the use of compounds of
formula 1 for the preparation of pharmaceutical formulations for
the treatment of diseases connected with the CCR3 receptor. A CCR3
receptor binding test showing this activity was already disclosed
in WO 2010 115836. Ki values for the compounds of formula 1 (human
Eotaxin-1 at human CCR3-Receptor) are shown in the table below. As
used herein, "activity" is intended to mean a compound
demonstrating an inhibition of 50% at 1 .mu.M or higher in
inhibition when measured in the aforementioned assays. Such a
result is indicative of the intrinsic activity of the compounds as
inhibitor of CCR3 receptor activity.
The examples of compounds of formula 1 can be synthesized according
to the description of WO 2010 115836, which is herewith
incorporated by reference. The salts of these examples can be
formed by crystallizing the free bases from a solution containing
HCl. Preferably the examples 1, 2 3, 4, 5, 6, 7, 8, 9 and 10 are in
form of the dihydrochloride.
TABLE-US-00009 hCCR3 # Structure Ki (nM) 1. ##STR00004## 10.4 2.
##STR00005## 3.2 3. ##STR00006## 3.5 4. ##STR00007## 4.3 5.
##STR00008## 4.6 6. ##STR00009## 4.0 7. ##STR00010## 5.2 8.
##STR00011## 2.3 9. ##STR00012## 4.2 10. ##STR00013## 1.7
Example for Degradation
High Performance Liquid Chromatography (HPLC) with a reversed phase
column and a gradient with buffer/acetonitrile and UV
quantification were used for the quantification of degradation
products
The stability results of storage under stress conditions (bottles
at 40.degree. C./60.degree. C.) and open storage at 25.degree.
C./60% r.h. for pure drug substance and different tablet
formulation provide evidence that due to the formulation signicant
stability improvement was achieved.
The drug substance stored open for one week at 25.degree. C./60%
r.h. liquefies, which is accompanied by degradation (total
degradation of 2.5%). Stored in a close container for 3 months a
total degradation of 43% was quantified.
The different formulation principles developed show under the same
conditions and similar packaging no degaradation (alu/alu blister
no degradation product >0.1% after 3 month) and under open
storage conditons at 25.degree. C./60% r.h. (1 week) a total
degradation of 0.7%.
According to internationally accepted guidelines (e.g. ICH Q3b) the
improved stability characteristics enable the administration of the
new chemical entity to patients.
Tablets
With the compounds above i.e. examples 1, 2, 3, 4, 5, 6, 7, 8, 9
and 10 in form of the hydrochloride or examples 1, 2 3, 4, 5, 6, 7,
8, 9 and 10 in form of the dihydrochloride the following
non-limiting examples for solid pharmaceutical compositions can be
made:
Example 1
Tablet Formulation--Wet Granulation
Copovidone is dissolved in ethanol at ambient temperature to
produce a granulation liquid. An active CCR3 antagonist ingredient
compound of formula 1, lactose and part of the crospovidone are
blended in a suitable mixer, to produce a pre-mix. The pre-mix is
moistened with the granulation liquid and subsequently granulated.
The moist granulate is optionally sieved through a sieve with a
mesh size of 1.6-3.0 mm. The granulate is dried at 45.degree. C. in
a suitable dryer to a residual moisture content corresponding to
1-3% loss on drying. The dried granulate is sieved through a sieve
with a mesh size of 1.0 mm. The granulate is blended with part of
the crospovidone and microcrystalline cellulose in a suitable
mixer. Magnesium stearate is added to this blend after passing
through a 1.0 mm sieve for delumping. Subsequently the final blend
is produced by final blending in a suitable mixer and compressed
into tablets. The following tablet composition can be obtained:
TABLE-US-00010 Component mg/tablet %/tablet Active ingredient
28.500 30.0 Crospovidone 1.500 1.6 Lactose 28.000 29.5 Copovidone
3.000 3.2 ->Total (granulate) 61.000 ->64.3 Microcrystalline
cellulose 31.000 32.6 Crospovidone 2.500 2.6 Magnesium stearate
0.500 0.5 Total 95.000 100.000
Example 2
Tablet Formulation--Melt Granulation
An active CCR3 antagonist ingredient compound of formula 1,
lactose, part of the microcrystalline cellulose, polyethylene
glycole, lactose and part of the crospovidone are blended in a
suitable mixer, to produce a pre-mix. The pre-mix is heated in a
high shear mixer and subsequently granulated. The hot granulate is
cooled down to room temperature and sieved through a sieve with a
mesh size of 1.0 mm. The granulate is blended with part of the
crospovidone and microcrystalline cellulose in a suitable mixer.
Magnesium stearate is added to this blend after passing through a
1.0 mm sieve for delumping. Subsequently the final blend is
produced by final blending in a suitable mixer and compressed into
tablets. The following tablet composition can be obtained:
TABLE-US-00011 Component mg/tablet %/tablet Active ingredient
28.500 30.0 Crospovidone 1.500 1.6 Lactose 11.000 11.6 Polyethylene
glycole 14.300 15.1 Microcrystalline cellulose 5.700 6.0 ->Total
(granulate) 61.000 ->64.3 Microcrystalline cellulose 31.000 32.6
Crospovidone 2.500 2.6 Magnesium stearate 0.500 0.5 Total 95.000
100.000
Example 3
Tablet Formulation--Hot Melt Granulation
An active CCR3 antagonist ingredient compound of formula 1, mannit,
polyethylene glycole and part of the crospovidone are blended in a
suitable mixer, to produce a pre-mix. The pre-mix is heated in a
high shear mixer and subsequently granulated. The hot granulate is
cooled down to room temperature and sieved through a sieve with a
mesh size of 1.0 mm. The granulate is blended with part of the
crospovidone and mannit in a suitable mixer. Magnesium stearate is
added to this blend after passing through a 1.0 mm sieve for
delumping. Subsequently the final blend is produced by final
blending in a suitable mixer and compressed into tablets. The
following tablet composition can be obtained:
TABLE-US-00012 Component mg/tablet %/tablet Active ingredient
28.500 30.0 Crospovidone 1.500 1.6 Mannit 16.700 17.6 Polyethylene
glycole 14.300 15.1 ->Total (granulate) 61.000 ->64.3 Mannit
31.000 32.6 Crospovidone 2.500 2.6 Magnesium stearate 0.500 0.5
Total 95.000 100.000
Example 4
Tablet Formulation--Hot Melt Extrusion
An active CCR3 antagonist ingredient compound of formula 1 and
stearic-palmitic acid are blended in a suitable mixer, to produce a
pre-mix. The pre-mix is extruded in a twin-screw-extruder and
subsequently granulated. The granulate is sieved through a sieve
with a mesh size of 1.0 mm. The granulate is blended with mannit
and crospovidone in a suitable mixer. Magnesium stearate is added
to this blend after passing through a 1.0 mm sieve for delumping.
Subsequently the final blend is produced by final blending in a
suitable mixer and compressed into tablets. The following tablet
composition can be obtained:
TABLE-US-00013 Component mg/tablet %/tablet Active ingredient
28.500 30.0 Stearic-palmitic acid 27.500 28.9 ->Total
(granulate) 56.000 ->58.9 Mannit 32.600 34.3 Crospovidone 5.600
5.9 Magnesium stearate 0.800 0.9 Total 95.000 100.000
Example 5
Tablet Formulation--Hot Melt Extrusion
An active CCR3 antagonist ingredient compound of formula 1 and
stearic-palmitic acid are blended in a suitable mixer, to produce a
pre-mix. The pre-mix is extruded in a twin-screw-extruder and
subsequently granulated. The granulate is sieved through a sieve
with a mesh size of 1.0 mm. The granulate is directly filled into
hard capsules. The following capsule composition can be
obtained:
TABLE-US-00014 Component mg/tablet %/tablet Active ingredient
70.000 70.0 Stearic-palmitic acid 30.000 30.0 ->Total
(granulate) 100.000 ->100.0 Capsule 90.000 -- Total 190.000
100.000
Example 6
Tablet Formulation--Roller Compaction
An active CCR3 antagonist ingredient compound of formula 1, part of
mannit and crospovidone and magnesium stearate are blended in a
suitable mixer, to produce a pre-mix. The pre-mix is compacted with
a roller compactor and subsequently granulated. Optionally, the
granulate is sieved through a sieve with a mesh size of 0.8 mm. The
granulate is blended with part of mannit and crospovidone in a
suitable mixer. Magnesium stearate is added to this blend after
passing through a 1.0 mm sieve for delumping. Subsequently the
final blend is produced by final blending in a suitable mixer and
compressed into tablets. The following tablet composition can be
obtained:
TABLE-US-00015 Component mg/tablet %/tablet Active ingredient
28.500 30.0 Crospovidone 1.400 1.5 Mannit 34.600 36.4 Magnesium
stearate 0.500 0.5 ->Total (granulate) 65.000 ->68.4 Mannit
27.000 28.4 Copovidone 1.600 1.7 Crospovidone 0.950 1.0 Magnesium
stearate 0.450 0.5 Total 95.000 100.000
Example 7.1
Tablet Formulation--Roller Compaction
An active CCR3 antagonist ingredient compound of formula 1 and
magnesium stearate are blended in a suitable mixer, to produce a
pre-mix. The pre-mix is compacted with a roller compactor and
subsequently granulated. Optionally, the granulate is sieved
through a sieve with a mesh size of 0.8 mm. The granulate is
blended with mannit and croscarmellose sodium in a suitable mixer.
Magnesium stearate is added to this blend after passing through a
1.0 mm sieve for delumping. Subsequently the final blend is
produced by final blending in a suitable mixer and compressed into
tablets. The following tablet composition can be obtained:
TABLE-US-00016 Component mg/tablet %/tablet Active ingredient
114.200 66.0 Magnesium stearate 1.800 1.0 ->Total (granulate)
116.000 ->67.0 Mannit 51.000 29.5 Croscarmellose sodium 3.500
2.0 Magnesium stearate 2.500 1.5 Total 173.000 100.000
Example 7.2
Tablet Formulation--Roller Compaction
An active CCR3 antagonist ingredient compound of formula 1 is
compacted with a roller compactor and subsequently granulated.
Optionally, the granulate is sieved through a sieve with a mesh
size of 0.8 mm. The granulate is blended with dibasic
calciumphosphate anhydrous, microcrystalline cellulose and
croscarmellose sodium in a suitable mixer. Magnesium stearate is
added to this blend after passing through a 1.0 mm sieve for
delumping. Subsequently the final blend is produced by final
blending in a suitable mixer and compressed into tablets. The
following tablet composition can be obtained:
TABLE-US-00017 Component mg/tablet %/tablet Active ingredient
114.000 66.0 Microcrystalline cellulose 17.400 10.0 Dibasic
calciumphosphate 32.100 18.5 Croscarmellose sodium 6.900 4.0
Magnesium stearate 2.600 1.5 Total 173.000 100.000
Example 8
Tablet Formulation--Roller Compaction
An active CCR3 antagonist ingredient compound of formula 1 and
magnesium stearate are blended in a suitable mixer, to produce a
pre-mix. The pre-mix is compacted with a roller compactor and
subsequently granulated. Optionally, the granulate is sieved
through a sieve with a mesh size of 0.8 mm. The granulate is
blended with microcrystalline cellulose and crospovidone in a
suitable mixer. Magnesium stearate is added to this blend after
passing through a 1.0 mm sieve for delumping. Subsequently the
final blend is produced by final blending in a suitable mixer and
compressed into tablets. The following tablet composition can be
obtained:
TABLE-US-00018 Component mg/tablet %/tablet Active ingredient
114.200 66.0 Magnesium stearate 1.800 1.0 ->Total (granulate)
116.000 ->67.0 MCC 51.000 29.5 Crospovidone 3.500 2.0 Magnesium
stearate 2.500 1.5 Total 173.000 100.000
Example 9.1
Coated Tablet Formulation
Tablet cores according above mentioned formulations can be used to
produce film-coated tablets. Hydroxypropyl methylcellulose (HPMC),
polyethylene glycol, talc, titanium dioxide and iron oxide are
suspended in purified water in a suitable mixer at ambient
temperature to produce a coating suspension. The tablet cores are
coated with the coating suspension to a weight gain of about 3% to
produce film-coated tablets. The following film coating composition
can be obtained:
TABLE-US-00019 Component mg/tablet %/tablet Hypromellose (HPMC)
2.40 48.0 Polyethylene glycol 6000 0.70 14.0 Titanium dioxide 0.90
18.0 Talcum 0.90 18.0 Iron oxide red 0.10 2.0 Purified water
(volatile component) -- -- Total 5.00 100.0
Example 9.2
Coated Tablet Formulation
Tablet cores according above mentioned formulations can be used to
produce film-coated tablets. Polyvinyl alcohol (PVA), polyethylene
glycol, talc, titanium dioxide and iron oxide are suspended in
purified water in a suitable mixer at ambient temperature to
produce a coating suspension. The tablet cores are coated with the
coating suspension to a weight gain of about 3% to produce
film-coated tablets. The following film coating composition can be
obtained:
TABLE-US-00020 Component mg/tablet %/tablet Polyvinyl alcohol (PVA)
2.00 40.0 Polyethylene glycol 6000 1.0 20.2 Titanium dioxide 1.11
22.1 Talcum 0.74 14.8 Iron oxide red 0.08 1.6 Iron oxide yellow
0.07 1.4 Purified water (volatile component) -- -- Total 5.00
100.0
Indications
The compounds of formula 1 as described above are useful for
manufacturing a pharmaceutical formulation for the prevention
and/or treatment of diseases wherein the activity of a
CCR3-receptor is involved.
Preferred is the manufacturing of a medicament for the prevention
and/or treatment of a wide variety of inflammatory, infectious, and
immunoregulatory disorders and diseases of the respiratory or
gastrointestinal complaints, inflammatory diseases of the joints
and allergic diseases of the nasopharynx, eyes, and skin, including
asthma and allergic diseases, eosinophilic diseases, infection by
pathogenic microbes (which, by definition, includes viruses), as
well as autoimmune pathologies such as the rheumatoid arthritis and
atherosclerosis, as well as diseases associated with abnormal
enhanced neovascularization such as age-related macular
degeneration (AMD), including dry age-related macular degeneration
(dAMD) and wet age-related macular degeneration (wAMD); diabetic
retinopathy and diabetic macular edema, retinopathy of prematurity
(ROP), central retinal vein occlusion (CRVO), nasal polyposis,
eosinophilic esophagitis, eosinophillic gastroenteritis (e.g.
eosinophilic gastritis and eosinophilic ententeritis),
hypereosinophilic syndrome and Churg Strauss syndrome.
Age-related macular degeneration (AMD) is a leading cause of
blindness worldwide. Most blindness in AMD results from invasion of
the retina by choroidal neovascularization. CCR3 is specifically
expressed in choroidal neovascular endothelial cells of AMD
patients. In an often used mouse animal model for AMD laser
injury-induced choroidal neovascularization was dimished by genetic
depletion of CCR3 or CCR3 ligands as well as by treatment of the
mice with an anti-CCR3 antibody or an CCR3 antagonist (Takeda et
al, Nature 2009, 460(7252):225-30)
Most preferred is the manufacturing of a medicament for the
prevention and/or treatment of e.g. inflammatory or allergic
diseases and conditions, including respiratory allergic diseases
such as asthma, perennial and seasonal allergic rhinitis, allergic
conjunctivitis, hypersensitivity lung diseases, hypersensitivity
pneumonitis, eosinophilic cellulites (e.g., Well's syndrome),
eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic
eosinophilic pneumonia), eosinophilic fasciitis (e.g., Shulman's
syndrome), delayed-type hypersensitivity, interstitial lung
diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD
associated with rheumatoid arthritis, systemic lupus erythematosus,
ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome,
polymyositis or dermatomyositis); non-allergic asthma; Exercise
induced bronchoconstriction; systemic anaphylaxis or
hypersensitivity responses, drug allergies (e.g., to penicillin,
cephalosporins), eosinophilia-myalgia syndrome due to the ingestion
of contaminated tryptophan, insect sting allergies; autoimmune
diseases, such as rheumatoid arthritis, psoriatic arthritis,
multiple sclerosis, systemic lupus erythematosus, myasthenia
gravis, immune thrombocytopenia (adult ITP, neonatal
thrombocytopenia, paediatric ITP), immune haemolytic anaemia
(auto-immune and drug induced), Evans syndrome (platelet and red
cell immune cytopaenias), Rh disease of the newborn, Goodpasture's
syndrome (anti-GBM disease), Celiac, Auto-immune cardio-myopathy
juvenile onset diabetes; glomerulonephritis, autoimmune
thyroiditis, Behcet's disease; graft rejection (e.g., in
transplantation), including allograft rejection or graftversus-host
disease; inflammatory bowel diseases, such as Crohn's disease and
ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis
(including Tcell mediated psoriasis) and inflammatory dermatoses
such as an dermatitis, eczema, atopic dermatitis, allergic contact
dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous,
and hypersensitivity vasculitis); erythema nodosum; eosinophilic
myositis, eosinophilic fasciitis; cancers with leukocyte
infiltration of the skin or organs; chronic obstructive pulmonary
disease, AMD, diabetic retinopathy and diabetic macular edema.
In another aspect of the invention preferred is the manufacturing
of a medicament for the prevention and/or treatment of diseases
selected from AMD, including dry age-related macular degeneration
(dAMD) and wet age-related macular degeneration (wAMD); diabetic
retinopathy and diabetic macular edema; and retinopathy of
prematurity (ROP).
* * * * *